Rational drug design Flashcards
what is lead optimisation
synthetic modification of a biologically active compound
- to fulfil all pharmacodynamic, pharmacokinetic, toxicological and formulator requirements for clinical usefulness
what is pharmacodynamics
study of the biochemical and physiological effects of the drugs and the mechanisms of drug action and the relationship between drug concentration and effect
what does improved pharmacodynamic activity lead to
- greater potency
- greater selectivity
what is pharmacokinetics
study of absorption, distribution, metabolism and excretion of bioactive compounds in a higher oraganism
what does improved pharmacokinetic activity lead to
- better bioavailability and absorption
- more advantageous distribution
- better metabolic profile and longer duration of action
- different excretion profile
what does improved toxicological profile lead to
toxicity is sometimes associated with particular structural moieties
what other reasons is lead optimisation carried out
- formulation
- chemical stability
- economic factors
- ease of synthesis
- ecological factors
- intellectual property and patent protection
what did the rational drug design for Levodopa and parkinsonism show
- observed that dopamine levels in patients were lower than in healthy people
- L dopa crosses BBB by active transport and is decarboxylated to dopamine
what can be used in molecular modelling to identify the pharmacore
- x ray crystallography- from bond distances can identify nature of the bonding interaction
- structural comparison of active compounds
- measuring possible conformations of many ligands
- predict most likely pharmacophoric descriptors
what can be used in molecular modelling to identify the active conformation
- x ray crystallography
- if have a crystal structure of target protein with ligand attached
- can establish the coordinates for the ligand and establish active conformation
- can establish coordinates for the target and model the binding site
what is computational drug discovery
quantum mechanics uses quantum physics to calculate properties of molecules by considering the interactions between electrons and nuclei of the molecule
what is involved in molecular modelling in computational drug discovery
- molecular orbital energies and coefficients
- heat of formation for specific conformations
- partial atomic charges
- electrostatic potentials
- bond dissociation energies
what is involved in the can model of molecular modelling
- bond lengths
- bond angles
- torsion angles
- process of iteration finds most stable structure
- 3d structures of drugs and targets
- interactions between drugs and targets
- bonding interactions
- shape, size and fit
what can be used to find lead activity molecules in molecular modelling
- can construct virtual libraries of molecules
- screen each molecule for best fit against defined criteria
- docking of ligand to target is simulated
what does a pharmacore define
- bonding interactions
- bond distances
- conformation and steric parameters
what is the de novo design in molecular modelling
- design molecules to fit target molecule
- molecules constructed from fragments that are typically found in existing drugs
- new ligands should be capable of being synthesised
- new molecular libraries can be designed on the basis of info obtained from de novo analysis
- generate new lead activity molecules
what are isosteres
molecules or ions of similar size containing the same number of atoms and valence electrons
what is isosterism
concept of making changes to molecules on the basis of isosteric substitutions
what are isosteric substitutions organised into
class I, II, III, IV, and V
give an example of what can be used as an oral hypoglycaemic agent alternative to tolbutamide
chlorpropamide has a longer duration of activity
- bd dosing instead of tds
give an example of class I isosteric substitutions
halogens, OH, NH2, CH3
what can isosteric replacements change
can change the nature of activity
- from agonist to antagonist
what are class II isosteric substitutions
O, S, Se, NH, CH2
what are class III isosteric substitutions
N–, CH–, P–, As–
what are class IV isosteric substitutions
–C–, Si, N+, P+
what are class V isosteric substitutions
in rings
- CH–CH, S, O, NH
give an example of a class II isosteric replacement
procainamide is less prone to hydrolysis than procaine and has a longer duration of action
what is a bioisostere
compound resulting from the exchange of an atom or a group of atoms with another broadly similar atom or group of atoms
what is the objective of bioisosteric replacement
to create a new compound with similar biological properties to the parent compound
what is bioisosterism
involves the interchange of groups or molecules having similar physical or chemical properties
- interchange maintains key biological properties
describe the properties of carbenicillin and its tetrazolyl analogue
- the a-carboxylic acid decarboxylates in the acid environment of the stomach to form benzyl penicillin
- loss of spectrum activity - the tetrazolyl analogue is orally active and doesn’t lose spectrum of activity
give examples of structural change that can occur in bioisosterism
- ring opening and closure
- reversal of groups
what are the consequences of structural change
- have produced a different chemical entity
- changes in size and shape of molecule
- changes in electronic distribution within molecule
- changes in lipid/water solubility
- changes in pka
- changes in chemical reactivity
- changes in biological activity- pharmacodynamics and pharmacokinetics
what can isosterism and bioisosterism be used to establish
can be used to establish structure activity relationships
- requires synthesis of many analogues
what are quantitative structure activity relationships
mathematical relationships linking chemical structure and pharmacological activity in a quantitative manner for a series of compounds
give the equation to represent biological activity
biological activity = f(transport + receptor binding)
what are the basic requirements in QSAR studies
- all analogs belong to a congeneric series
- all analogs exert the same moa
- all analogs bind in a comparable manner
- binding affinity is correlated to interactional energies
- biological activities are correlated to binding affinity
what are the pharmacodynamic factors affecting QSAR
- shape, size and orientation in space of functional groups
- complementarity between drug and target
- bonding interactions
what are the pharmacokinetic factors
absorption, distribution, metabolism and excretion
what is the difference in log P values due to
due to the influence of the substituent
what is the substituent hydrophobicity constant
- if we measure log P value for a molecule and then for a structurally similar derivative, the difference in lipophilicity must be due to the different substituent
- in broadly similar structures, the substituent hydrophobicity constant for a particular substituent will be very similar and so the constant can be applied to new classes of molecules
what is the equation for the substituent hydrophobicity constant (pi)
substituent hydrophobicity constant= log Px - log Ph
what do substituent hydrophobicity constant values depend on
- depend on environment
- aromatic systems are different from aliphatic
what are the applications of substituent hydrophobicity constant values
- synthesis a small number of analogues
- compare activity in the series
- if establish that lipophilicity is important for activity, then are able to predict what bioisosteric replacement might be likely to improve activity
what is the reactivity of molecules dependent on
- functional groups
- electron distribution within the molecule
what are the impacts of substituents on pKa
electron withdrawing or electron donating properties of the R group affect pKa
what is the Hammett substituent constant
Hammett substituent constant= logKx - logKh
- pKa is the negative log of the dissociation constant
what is the Hammett substituent constant
a measure of the electron withdrawing or electron donating ability of a substituent
what is the effect of electron withdrawing and electron donating on Hammett substituent constant values
- electron withdrawing has positive constant values
- electron donating has negative constant values
what are the applications of Hammett substitution constant (o)
- can have both resonance and inductive effects
- position on the aromatic ring is important
- can only be used for aromatic substituents and only suitable for drugs containing aromatic rings
what are the electronic effects for aliphatic substituents
- calculated from the rates of hydrolysis of a series of aliphatic esters
- different ester groups will hydrolyse at different rates
- the rate of hydrolysis is a reflection on the inductive effect of the substituent on the reactivity of the ester
describe the effects of electron donating and withdrawing groups on the rate of hydrolysis
- electron donating groups reduce rate of hydrolysis and have negative values
- electron withdrawing groups increase rate of hydrolysis and have positive values
what is Tafts steric factor
- rates of hydrolysis are affected by steric effects and are obtained by measuring hydrolysis under different conditions
- under acidic conditions only, steric factors are important whereas under basic conditions, both steric and inductive factors are relevant
- by determining the effet of a substituent under both alkaline and acidic conditions, a parameter for the steric effect is determined
what are the other measures for steric factors
- molar refractivity- measure of the volume occupied by an atom or group of atoms
- the Verloop steric parameter- calculates steric substituent values from standard bond angles
- unlike Tafts steric factor, verloop steric parameters can be calculated for nay substituent
what is the Hansch equation
Log(1/C0= k1 logP + k2 o +k3Es + k4
- relates actiivity to a combination of factors
what is the Hansch analysis
the investigation of the quantitative relationship between biological activity of a series of compounds and their physicochemical substituent or global parameters representing hydrophobic, electronic, steric and other effects
what does electronic effects influence
influences the reactivity of molecules
what is a Craig plot
- scatter diagram
- position is determined by (pi) and (o) values for a substituent
- can be constructed for any pair of parameters (pi, o, or Es)
what do QSAR studies tend towards
tend towards very lipophilic molecules
- aqueous solubility is compromised
what is Lipinskis rule of 5
poor absorption and permeation are more likely when the drug molecule has:
- >5 H bond donors
- MW>500
- Log P>5
- >10 H bond acceptors
what are the exceptions to Lipinskis rule
- substrates for biological transporters are exceptions
what additional properties do structure property relationships include compared to SARs
- metabolic stability
- permeability
- chemical stability
